Human T-cell leukemia virus type I (HTLV-I) has been implicated in both human T-cell malignancy and in a chronic debilitating neurologic disorder with similarities to multiple sclerosis, known as HTLV-I-associated myelopathy (HAM). Although pathogenetic mechanisms are partially understood in the context of HTLV-I-associated leukemia, the relationship between HTLV-I infection and development of neurologic disorders is unclear. We wish to explore possible mechanisms underlying HAM by determining whether genetic and/or biological differences exist between HTLV-I isolates obtained from the peripheral blood and cerebrospinal fluid of HAM patients as compared to isolates obtained form asymptomatic carriers or patients with leukemia. We will compare HTLV-I isolates in contexts designed to minimize irrelevant biological variation, such as in a transfusion recipient who developed HAM, compared to those obtained from the asymptomatic HTLV-I-infected blood donor; from myelopathy patients and uninfected patients in a recently identified highly infected, heavily intermarried ethnic group; and in the cerebrospinal fluid as opposed to the peripheral blood of a single HAM patient. We will determine whether these HTLV-I isolates can replicate transiently or stably in cell lines/cultures derived from tissues of human central nervous system origin. We will compare levels of HTLV-I replication in HAM patients to those in symptomatic individuals using a novel adaptation of the polymerase chain elongation technique for analysis of both DNA and RNA levels. Finally, as preliminary evidence points to potentially important autoimmune mechanisms in HAM, we will determine whether antibody production plays a role in pathogenesis of HAM through assay of antibodies contained within the cerebrospinal fluid for reactivity to normal brain antigens encoded by a human brain cDNA library. If autoimmune antibody specificities are defined, we will immortalize antibody-producing B-cell lines from HAM patients' cerebrospinal fluid to obtain monoclonal reagents for further studies. This combined molecular virologic and immunological approach should markedly increase our understanding of pathogenetic mechanisms in HAM and other neurological disorders caused by human retroviruses.